1. Field of the Invention
The present invention relates to substituted cyclic ketones and substituted cyclic enones, or substituted cyclopentanone and cyclohexanone derivatives and substituted cyclopentenone and cyclohexenone derivatives, which are useful as intermediates for pharmaceutical products and agricultural chemicals and especially useful for the synthesis of prostaglandins, and also to a process for producing the same.
2. Description of the Prior Art
Substituted cyclopentanone derivatives and .alpha.-substituted cyclopentenone derivatives are attracting attention because of their usefulness as intermediates for pharmaceutical products and agricultural chemicals. They are useful especially as intermediates for prostaglandins having strong physiological activities.
Heretofore, there are several known processes for producing prostaglandins. According to one of them, prostaglandin E is produced from a cyclopentenone derivative having no substituent at the .beta. position, by the so-called two-component reaction represented by the following equation. (M. J. Weiss, Journal of Organic Chemistry, vol. 44, p. 1439, 1979). ##STR1## (where THP denotes a tetrahydropyranyl group, Me denotes a methyl group, and Ph denotes a phenyl group.)
There are several known processes for producing intermediates which can be made into such a cyclopentenone derivative having no substituent at the .beta. position ("Prostaglandins and related physiologically active substances", pp. 89.about.92, 1981, by Terashima, Sakai, and Yamamoto). These processes, however, have some disadvantages when put to industrial use.
The other known processes for producing prostaglandins include the synthesis of prostaglandin F.sub.2.alpha. by the coupled addition reaction represented by the following equation [G. Stark et al., J. Am. Chem. Soc., vol. 97, 4745, p. 6260, (1975)] ##STR2##
According to the above-mentioned process for synthesis, prostaglandin F.sub.2.alpha. can be obtained in a high yield from the compound IVa'. In addition, it is possible to change the .alpha. chain as desired by properly selecting the reagent for coupled addition.
The known process for producing the compound IVa' has a disadvantage that the yield is low, the reagent used for synthesis is expensive, and usually the resulting compound IVa' is not optically active but is of racemic modification [D. R Morton et al., J. Org. Chem., vol. 43, p. 2102, (1978); A. P. Kodivsky et al., J. Org. Chem., vol. 49, p. 2301, (1984)]. For this reason, there is a demand for a process for producing prostaglandins in an industrially advantageous manner.
The present invention was completed with the foregoing in mind. Accordingly, it is an object of the present invention to provide new useful substituted cyclopentanone and cyclohexanone derivatives and substituted cyclopentenone and cyclohexenone derivatives from which prostaglandins can be produced in an industrially advantageous manner. It is another object of the present invention to provide a process for producing such derivatives.
In order to achieve the above-mentioned objects, the present inventors carried out a series of researches, which led to the findings that those compounds represented by the following formulas are useful as intermediates for the synthesis of prostaglandins. ##STR3##
In the above formulas:
R.sup.1 denotes a-hydrogen atom; a substituted or unsubstituted C.sub.1-10 alkyl group, alkenyl group, or alkynyl group; or a substituted or unsubstituted phenyl group.
R.sup.2 denotes a substituted or unsubstituted C.sub.1-10 alkyl group, alkenyl group, alkynyl group, alkylthio group, alkylamino group, alkylsilyl group, alkyl tin group, or cyano group.
R.sup.3 and R.sup.4 each denotes a substituted or unsubstituted C.sub.1-10 alkyl group; a substituted or unsubstituted phenyl group; and R.sup.3 and R.sup.4 may be the same or different from each other.
R.sup.5 denotes a substituted or unsubstituted C.sub.1-15 alkyl group, alkenyl group, or alkynyl group.
M.sup.1 and M.sup.2 each denotes a metal selected from Li, Na, K, Mg, Ca, Ti, Zr, Ni, Cu, Zn, Al, and Sn, or a group containing said metal.
X denotes (.alpha.-OZ, .beta.-H) or (.alpha.-H, .beta.-OZ).
Y denotes (.alpha.-OZ', .beta.-H) or (.alpha.-H, .beta.-OZ').
Z and Z' each denotes a hydrogen atom or a protective group for the hydroxyl group; and Z and Z' may be the same or different from each other.
W denotes CHR.sup.1, (.alpha.-CHR.sup.1 OH, .beta.-H), or (.alpha.-H, .beta.-CHR.sup.1 OH).
V denotes (.alpha.-CHR.sup.1 OH, .beta.-H), or (.alpha.-H, .beta.-CHR.sup.1 OH).
U denotes (.alpha.-H, .beta.-R.sup.5) when X is (.alpha.-OZ, .beta.-H) and also denotes (.alpha.-R.sup.5, .beta.-H) when X is (.alpha.-H, .beta.-OZ).
n is 1 or 2.
In other words, the present inventors found the following. Upon cyclization of the compound represented by the formula [V] by the aid of a hypohalogenite or a halogen gas in combination with a base, there is obtained the new compound [I], which can be converted into another new compound [II] (including [IIa] and [IIb]). To be more specific, upon hydrogenation-hydrolysis of the new compound [I] in the presence of a hydrogenation catalyst, there is obtained the new compound [IIa]. And, upon sulfonylation of the new compound [IIa] in the presence of a base, followed by desulfonation, there is obtained the new compound [IIb].
The present inventors also found the following. Upon reaction of the new compound [IIb] with the compound represented by the formula [VI], there is obtained a compound represented by the formula [III] which includes the new compound [IIIa]. This new compound [IIIa] is obtained by the reaction of the new compound [IIb] with the compound [VII]. This new compound [IIIa] is also obtained by the sulfonylation of the new compound [IIa] in the presence of a base, followed by desulfonation and reaction with a compound of the formula [VII]. Upon reaction of the new compound [IIIa] with a compound represented by the formula [VIII], there is obtained a compound represented by the formula [IV].
The present inventors found that the compounds represented by the formulas [II] ([IIa] and [IIb]), [III], [IIIa], and [IV] are intermediates useful for the synthesis of prostaglandins. These findings led to the present invention.
Accordingly, the present invention provides:
(1) the new compound [I] and a process for producing the same; PA1 (2) the new compounds [II] ([IIa] and [IIb]) and a process for producing the same. PA1 (3) a process for producing the compound [III], and the new compound [IIIa] and a process for producing the same. PA1 (4) a process for producing the compound [IV].